Description: This is the final version. It was first published by BioMed Central at http://www.cardiab.com/content/14/1/61.

Abstract: Background: Type-2 diabetes is associated with systemic inflammation and higher C-reactive protein (CRP) levels.
However, the longitudinal association of CRP and haemoglobin-A1c (HbA1c) has not been described in large prospective
studies. Understanding such associations may shed light on the role of inflammation in development of type-2 diabetes
and its complications such as cardiovascular diseases.
Methods: EPIC-Norfolk is a cohort study of men and women aged 40–79 years at time of recruitment (1993–1997).
Serum CRP (mg/l) was measured using a high-sensitivity assay at baseline and 13-years follow-up. HbA1c (%) was
measured at baseline, 4, and 13 years. Participants were excluded if they were diagnosed with diabetes or were
taking diabetes medication. Data on at least one measurement of CRP and HbA1c was available for 14228 participants
(55 % of the cohort).
Results: In the cross-sectional analysis of baseline data, a 1-SD higher loge-CRP (about three-fold higher CRP) was associated
with 0.06 (95 % CI 0.04, 0.08) higher HbA1c (%) adjusted for potential confounders. In longitudinal analysis using multivariable
linear mixed models, change in CRP over 13 years was to a similar extent positively associated with increase in HbA1c,
such that 1-SD higher longitudinal change in loge-CRP was associated with 0.04 (95 % CI 0.02, 0.05) increase in HbA1c.
Conclusion: In this study we found longitudinal observational evidence suggesting that increase in systemic inflammation
is associated with an increase in HbA1c and thus systemic inflammation may have a role in development of type-2
diabetes and its complications.

Sponsorship: We thank all study participants, general practitioners and the EPIC-Norfolk
study team for their contribution. The EPIC-Norfolk study is supported by
funding from the Medical Research Council and Cancer Research UK. SA is
supported by the Gates Cambridge scholarship. Funding sources did not have
a role in the design and conduct of the study, the collection, management,
analysis, and interpretation of the data or the preparation, review, approval, or
decision to submit the manuscript.